The following background section is presented for informational purposes only, and does not constitute an admission that any of the material presented in this section qualifies as prior art to the current application.
This disclosure relates to methods and systems for exploiting human circadian and ultradian control systems with different temporal and optical projections of selected wavelengths of infrared energy, specifically in and around the human integumentary system:
The present disclosure generally relates to methods and systems for exploiting human or animal circadian and ultradian control systems with different temporal and optimal projections of selected wavelengths of infrared energy in and around the human integumentary system. The science describing these devices and methods will be termed chrono-photo-biology by the current inventor. Human circadian control systems function as a result of a series of endogenous molecular clocks that govern 24-hour physiologic and cellular metabolic fluctuations. Ultradian control systems govern recurrent biological periods or cycles that are repeated throughout a 24-hour “circadian” day. These Circadian and ultradian fluctuations drive cellular metabolism, cell cycle events, angiogenesis, DNA repair, cellular apoptosis, immune functions and most other metabolic and physiologic systems in the human integumentary system.
On a cellular level, the circadian and ultradian clocks are coordinated by endogenous physiological rhythms, and work in a synchronous manner, so that specific spatiotemporal cellular events in the cell cycle such as quiescence and proliferation (mitosis) can be predicted in most tissues. With chrono-photo-biology, improved photobiologic treatment efficacy can be performed, when specifically titrated therapies are given in times of optimum tolerability, which can be predicted based on a patients endogenous circadian and ultradian rhythms. The recognition of this circadian and ultradian timing for hormonal and cell cycle regulation in the human integumentary system, and its exploitation as a method of augmenting photobiologic therapy, has the capacity to modify and vastly improve induced photobiologic effects. Positive cellular responses to phototherapy can increase many fold, in areas such as fibroblast and keratinocyte optically directed photo-taxis and cell translocation, wound healing, skin growth, local endogenous leptin secretion, and enhanced collagen deposition. The present invention particularly, relates to methods and systems for exploitation of human circadian and ultradian clocks, as a method of improving photobiologic therapy in and around the human integumentary system.
An abundance of studies spanning the past three decades have shown selected beneficial effects of various light therapies on human epidermal and dermal tissues. These positive effects have been described as the stimulation of DNA and RNA synthesis, promotion of cell adhesion, acceleration of wound healing, extracellular matrix proliferation, fibroblast collagen production, increased production of granulation tissue and reduction of the inflammatory response. While several of these different occurrences (and increased or decreased effects) have been researched in vitro and in vivo, to the applicant's knowledge there are no studies that have selectively researched the effect of light therapy, when tied to the inherent circadian and ultradian rhythms that govern human integumentary cells and their biochemistry and metabolism. Studies of various calibers, in the last three decades have instead focused largely on different “instruments and mechanisms of light therapy” to effect cellular signaling molecules such as ATP, cellular metabolites, and various forms of reactive oxygen species, all in the absence of cell cycle temporal data and components.
The vast majority of light therapy studies in the last three decades have focused on wound healing. These studies have generated a tremendous quantity of information concerning cellular proliferative effects, cell motility, and various stimulatory effects. However, it is rarely the case, that a given data set (form any in vitro or in vivo study) can be easily reproduced with a photo-therapy protocol or device. Many researchers have argued that the reason for this difficulty is that most studies do not adequately disclose one or more of the important parameters of the treatment such as (a) light output power, (b) irradiation treatment time, (c) irradiation spot size and/or (d) the degree of wavelength purity of the treatment device.
The present applicant has realized that the field of infrared phototherapy may be significantly advanced by study of the effects of infrared phototherapy from the perspective of the circadian and ultradian rhythms that govern the cells being treated in and around the human integumentary system. For example, in the plethora of studies that have been conducted looking for augmentation of fibroblast and keratinocyte motility, to the applicant's knowledge not a single one has described the therapy in temporal terms with respect to the G1/S phase of the 24-hour cell cycle. This would be vital information, as the G1/S phase (described below) is when human fibroblasts and keratinocytes have the greatest ability to express motility and translocate into a wound environment.
For the last 30 years, there has been a lack of appreciation of the spatiotemporal cellular coordination in the cell cycle when designing and performing infrared photo-therapy studies. This causes primary inaccuracies in data and results, as the capacity of cell motility and translocation is depressed at various times in the cell cycle, along with the fact that the majority of cellular energy and resources are being used for other vital processes like DNA replication and cytokinesis. These are not opportune times for infrared irradiation, if the effect that you desire is cell motility or collagen deposition. Infrared irradiation at these times, would actually act as a chrono-disruptive force, and not as an additive benefit. As far as the applicant is aware, infrared circadian and ultradian spatiotemporal cellular coordination, which is described herein has hitherto never previously been proposed to augment or increase the potential benefits or inhibit potential detriments to performing photo-therapy (in vitro or in vivo) on human integumentary cells and tissues.
In some aspects, the present disclosure advantageously leverages the discovery that specific narrow wavelengths of infrared energy, delivered at the correct dose, are not the only vital parameters necessary to enable efficacious therapy. The present disclosure brings to bare devices and methods to (a) analyze and (b) produce photo-therapy at the proper circadian and ultradian spatiotemporal windows for desired events, along with the most efficacious dispersion of energy during cell cycle events.
Optically based infrared photo-therapy generated and delivered within specific ultradian and circadian parameters based on a patient's own endogenous temporal rhythms has never been previously envisioned or studied in the history of photo-therapy. Merely it has been known that circadian and ultradian rhythms exist, and that their properties and repeating nature govern a plethora of cellular events.
As an example of this omission of circadian and ultradian spatiotemporal understanding can be seen in the recent detailed and comprehensive laser reviews (2010 Peplow et al and 2012 AlGhamdi et al) entitled “Laser photo-biomodulation of proliferation of cells in culture: a review of human and animal studies.” and “Low-level laser therapy: a useful technique for enhancing the proliferation of various cultured cells”. Therein, where approximately 200 articles were reviewed, only three mentions could be found of any researchers that temporally synchronized the cell cycle of the cells being studied. Without this basic measure as a control factor, for whether the cells being studied were in a specific point of interphase or mitosis, there can be little hope of duplicating and reproducing data and results. Furthermore, even in those few cases where some level synchronization was provided, no effort was made to correlate the application of treatment to selected phase in the cell cycle.
In another example, (Bahle 2012) writing a detailed review of phototherapy for Diabetic ulcers, did not list a single reference to circadian and ultradian spatiotemporal coordination with the photo-therapy or irradiation, from any studies in the review.
In another example (Huang 2009) writing a detailed review of Low Level Light therapy, with 111 references, did not mention once the circadian and ultradian spatiotemporal stage of the cell cycle, in the cells being tested and results being reported. There was no mention if the cells were at specific point of interphase or mitosis, and yet remarkably, with this missing cell cycle information, Huang et al concludes that, “In general, fluences of red or NIR as low as 3 or 5 J/cm^2 will be beneficial in vivo, but a large dose like 50 or 100 J/cm^2 will lose the beneficial effect and may even become detrimental” Statements like this are widespread throughout the literature, but cannot be supported or reproduced in a meaningful way, as there is no correlation to the spatio-temporal phase of the cell cycle that these cells were in when they were irradiated. Hence, the data cannot be reproduced, and there is no control to see if in fact the photo-therapy was beneficial or chrono-disruptive, based on where in the cell cycle the cells were temporally at the time of irradiation.